Every year, thousands of humans suffer traumatic brain injury (TBI) and most of the survivors manifest moderate to severe neurological dysfunction. Currently no known therapies that can prevent secondary neuronal death and/or promote neurological recovery after TBI in humans are available. Inflammation that starts within minutes and sustains for days after brain injury is thought to promote the secondary neuronal death and thus motor dysfunction. As controlling inflammation at the level of transcription is an effective strategy to prevent the neuronal damage, the goal of this proposal is to evaluate the efficacy of the transcription factor PPAR3 agonist rosiglitazone in preventing neuronal death and neurological dysfunction following TBI in adult mice. Previous studies showed that acute treatment with statins also induce neuroprotection following TBI, which is independent of their capability to lower cholesterol. Statins increase PPAR expression which is thought to mediate some of the pleiotropic beneficial effects of statins after an injury. Hence, we wish to test if the therapeutic potential and the window of benefit of rosiglitazone treatment following TBI can be enhanced by co-treating the animals with simvastatin. As both these compounds are FDA-approved, if proven beneficial, the combination can be quickly translated into clinical use to minimize the neurological deficits following TBI in humans. PUBLIC HEALTH RELEVANCE: Traumatic brain injury is a leading cause of disability in the world with few current therapeutic options. This proposal wishes to evaluate if a combination therapy with rosiglitazone and simvastatin (two FDA-approved drugs) can prevent the secondary neuronal death and thus neurological dysfunction after traumatic brain injury in mice. The ultimate goal is to identify drugs that benefit the recovery of brain trauma patients.